Primordial Germ Cells

Primordial germ cells are the earliest identifiable precursors of the germ cell lineage, the cells from which all future gametes derive. They are set aside as a distinct population remarkably early in development, well before the gonads begin to form.

They first become identifiable around week 3, among the extraembryonic mesoderm cells in the wall of the yolk sac, close to the origin of the allantois.

Their early segregation from the somatic cell lineages of the embryo proper is a defining feature of germ cell biology.

Because they are set aside this early, primordial germ cells largely avoid the epigenetic and lineage-restriction changes that somatic cells undergo. This property relates directly to their eventual capacity, once matured into gametes, to give rise to an entirely new individual.

Primordial germ cells undergo an extensive, precisely directed migration from their extraembryonic site of origin to the genital ridges. These are the paired regions of intermediate mesoderm on the posterior abdominal wall that will develop into the gonads.

Migration begins around week 4. The cells move from the yolk sac wall along the dorsal mesentery of the developing hindgut. This route takes them through the wall of the primitive gut tube itself before they emerge and continue toward the posterior body wall.

By around week 5 to 6, the migrating cells reach and colonise the genital ridges, arriving at the site where the gonad will subsequently form.

Migration is guided by chemotactic signalling from the genital ridge, which attracts the cells toward their target, and by cues within the surrounding tissue that constrain the pathway. The cells continue to proliferate by mitosis throughout the journey, so the population arriving at the genital ridge is much larger than the one that set out from the yolk sac wall.

Once primordial germ cells reach and colonise the genital ridge, they continue to proliferate, and their arrival is essential for normal gonadal development to proceed: the genital ridge alone, without colonisation by primordial germ cells, does not develop into a properly organised, functional gonad.

Within the developing gonad, primordial germ cells interact with the surrounding somatic cells of the genital ridge. It is this interaction, rather than the primordial germ cells acting in isolation, that drives formation of the specific supporting cell populations characteristic of the testis or ovary.

These are Sertoli cells and, spermatogonia in the male, and granulosa cells and, oogonia in the female.

The primordial germ cells themselves go on to become the oogonia or spermatogonia, the direct precursor population from which gametogenesis proper subsequently proceeds.

Failure of primordial germ cells to complete their normal migratory route, or migration to an ectopic location outside the genital ridge, has clinically recognised consequences.

If too few cells reach the genital ridge, gonadal development is impaired, since normal gonadal organisation depends on adequate colonisation. Inadequate colonisation is one contributing mechanism in some forms of gonadal dysgenesis, in which the gonad fails to develop into a normal, functional testis or ovary.

Cells that migrate along an aberrant path, or fail to migrate and remain near their original extraembryonic or intra-abdominal location, can persist at that ectopic site. In later life they can give rise to extragonadal germ cell tumours.

These tumours arise at points along the normal migratory pathway, most classically in the midline of the body: the sacrococcygeal region, mediastinum and pineal region, rather than within the gonad.

Recognising that these tumours arise from mislocated primordial germ cells explains their characteristic anatomical distribution. It also explains their capacity, like gonadal germ cell tumours, to differentiate along multiple tissue lineages when they form a teratoma.